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Anti-tweakr antibodies and uses thereof

a technology of anti-tweakr and antibodies, which is applied in the field of anti-tweakr antibodies, can solve the problems of lack of species cross-reactivity, lack of e.g., and less clear signaling pathways responsible for cell killing via tweakr, and achieve the effect of increasing efficacy

Inactive Publication Date: 2016-08-18
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a new antibody that can be used alone or together with other medications. It can also be modified to increase its effectiveness. For example, it can be attached to a drug that can target and kill specific cells. This would make the antibody more effective in treating certain diseases.

Problems solved by technology

However, the signaling pathways responsible for cell killing via TWEAKR are less clear, as the TWEAKR lacks a characteristic “death domain”.
A further limitation of PDL-192 is the lack of species cross-reactivity, especially mouse and rat, not allowing e.g. assessment of common pre-clinical studies as toxicological studies.

Method used

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  • Anti-tweakr antibodies and uses thereof
  • Anti-tweakr antibodies and uses thereof
  • Anti-tweakr antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Antibody Generation from Dyax Antibody Library

[0406]A fully human antibody phage display library (Hoet R M et al, Nat Biotechnol 2005; 23(3):344-8) was used to isolate TWEAKR-specific, human monoclonal antibodies of the present invention by protein panning (Hoogenboom H. R., Nat Biotechnol 2005; 23(3):1105-16) with dimeric Fc-fused extracellular domains of human and murine TWEAKR as immobilized target.

TABLE 1List of recombinant antigens used for antibody selectionNomenclatureDescriptionSEQ ID NOTPP-599HUMAN-TNFRSF12Aaa28-80-hIgG1-Fc138TPP-601MURINE-TNFRSF12Aaa28-80-hIgG1-Fc137

[0407]The antigens were biotinylated using an approximately 2-fold molar excess of biotin-LC-NHS (Pierce; Cat. No. 21347) according to manufacturer's instructions and desalted using Zeba desalting columns (Pierce; Cat. No. 89889). Washed Magnetic beads (Dynabeads) were incubated o / n with 200 nM of biotinylated human antigen at 4° C. and blocked for 1 h at 4° C. with blocking buffer (PBS with 3% BSA, 0.05% Tween...

example 2

Biochemical Characteristics of the Antibody

Determination of Binding Affinities by Biacore Analysis:

[0414]Binding affinities of anti-TWEAKR antibodies were determined by surface plasmon resonance analysis on a Biacore T100 instrument (GE Healthcare Biacore, Inc.). Antibodies were immobilized onto a CM5 sensor chip through an indirect capturing reagent, anti-human IgG(Fc). Reagents from the “Human Antibody Capture Kit” (BR-1008-39, GE Healthcare Biacore, Inc.) were used as described by the manufacturer. Anti-TWEAKR antibodies were injected at a concentration of 10 μg / ml at 10 μl / min for 10 sec.

TABLE 3List of recombinant antigen (TWEAKR) used for affinity measurementCat. No.(FitzgeraldSEQNomenclatureDescriptionOriginInc)ID NOTPP-2305hTNFRSF12Aaa28-80Human30R-AT080168

TABLE 4List of antibodies used for affinity measurementsSEQ ID NONomenclatureDescriptionLight chainHeavy chainP3G5 (TPP-Murine IgG2a1211222195)P4A8 (TPP-Human IgG11251261324)P2D3 (TPP-Murine IgG2a1311322196)136.1 (TPP-Murin...

example 3

Binding of Anti-TWEAKR Antibodies to Cell Surface of Cancer Cell Lines

[0443]To determine the binding characteristics of the anti-TWEAKR antibodies on mouse and human cancer cell lines, binding was tested by flow cytometry to a panel of cell lines. Adherent cells were washed twice with PBS without Ca and Mg (Biochrom #L1825: aqueous solution containing 8000 mg / l NaCl, 200 mg / l KCl, 1150 mg / l Na2HPO4, and 200 mg / l KH2PO4) and detached by enzyme-free PBS based cell dissociation buffer (Invitrogen). Cells were suspended at approximately 105 cells / well in FACS buffer (PBS without Ca / Mg, containing 3% FCS, Biochrom). Cells were centrifuged (250 g, 5 min, 4° C.) and supernatant discarded. Cells were resuspended in dilutions of the antibodies of interest (10 μg / ml in 80 μl if not indicated otherwise) in FACS buffer, and incubated on ice for 1 h. In the following cells were washed once with 1000 cold FACS buffer and 80 μl secondary antibody diluted at 1:150 (PE goat anti-human IgG, Dianova #...

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Abstract

The present invention provides recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for the TWEAKR (TNFRSF12A, FN14). The antibodies, accordingly, can be used to treat tumors and other disorders and conditions associated with expression of the TWEAKR. The invention also provides nucleic acid sequences encoding the foregoing antibodies, vectors containing the same, pharmaceutical compositions and kits with instructions for us.

Description

[0001]The present invention provides recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for the TWEAKR (TNFRSF12A, FN14).[0002]The antibodies, accordingly, can be used to treat tumors and other disorders and conditions associated with expression of the TWEAKR. The invention also provides nucleic acid sequences encoding the foregoing antibodies, vectors containing the same, pharmaceutical compositions and kits with instructions for use.BACKGROUND OF THE INVENTION[0003]Antibody-based therapy is proving very effective in the treatment of various cancers, including solid tumors. For example, HERCEPTIN® has been used successfully to treat breast cancer and RITUXAN® is effective in B-cell related cancer types. Central to the development of a novel successful antibody-based therapy is the isolation of antibodies against cell-surface proteins found to be preferentially expressed on tumor cells that are able t...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61K49/00A61K31/44A61K31/4745A61K31/282A61K31/513A61K47/48A61K39/395
CPCA61K47/48384C07K2317/55A61K49/0032A61K49/0058C07K16/2878A61K2039/505C07K2317/34C07K2317/56C07K2317/565C07K2317/73C07K2317/75C07K2317/77A61K39/39558A61K31/513A61K31/4745A61K31/44A61K31/282C07K2317/622C07K2317/92C07K2317/54C07K2317/24C07K2317/21C07K16/2863A61K2039/507A61K47/48569A61K47/48561A61K47/6803A61K47/6849A61K47/6851A61P35/00A61P35/04A61P43/00
Inventor VOTSMEIER, CHRISTIANHAMMER, STEFANIEGRITZAN, UWEBERNDT, SANDRAZUBOV, DMITRYLINDEN, LARSCHRISTIAN, SVENHARRENGA, AXELBIRKENFELD, JORGFREIBERG, CHRISTOPHGOLFIER, SVENEICKER, ANDREAGREVEN, SIMONESTELTE-LUDWIG, BEATRIXRASCHKE, MARIAN
Owner BAYER PHARMA AG
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